P1202: INTENDED USE OF GLUCARPIDASE IN PATIENTS WITH CENTRAL NERVOUS SYSTEM LYMPHOMA AND IMPAIRED RENAL FUNCTION – THE VALIDATE STUDY
Authors: S. Liebig, S. Burock, I. Merz, F. Knörnschild, P. Kießling, K. Kappert, U. Keller, S. Schwartz
Journal: HemaSphere (2022)

Background: Central nervous system lymphoma (CNSL) could occur as a primary disease or as a secondary manifestation of a systemic lymphoma; most patients (pts) with primary CNSL are diagnosed at an age >60 years. High-dose Methotrexate (HD-MTX) is an essential backbone of established treatment regimens, but chronic renal failure inevitably results in delayed MTX elimination, prolonged drug exposure and enhanced toxicities. Thus, chronic renal failure limits MTX-based therapies in adequate doses in pts with CNSL. Glucarpidase, approved for use in pts with delayed MTX clearance, is a zinc-dependent enzyme, which rapidly cleaves MTX into non-toxic metabolites and offers an alternative route of MTX elimination. Aims: The ongoing phase I/II VALIDATE study evaluates the safety as well as pharmacological efficacy (primary study endpoints) of intended and repeated use of Glucarpidase following HD-MTX in pts with CNSL and impaired renal function. The pharmacological efficacy of Glucarpidase will be assessed by determining the immediate and sustained reduction of MTX plasma concentrations after Glucarpidase administration, in addition to leucovorin. Methods: Pts with histologically confirmed CNSL and renal insufficiency, defined as either i) (estimated) glomerular filtration rate of 40–80 mL/min, or ii) experienced renal failure during a previous HD-MTX treatment, defined as doubling of blood creatinine compared to the baseline value, are eligible for study inclusion. Study pts may receive up to 6 cycles of HD-MTX (additional Rituximab prior HD-MTX is allowed as standard of care treatment) at MTX dose levels of 3.0 or 3.5 or 4.0 g/m2 body surface area administered over 4 hours (6 pts per dose level). Treatment cycles are repeated every 14 days (maximum interval 28 days). A fixed dose of 2000 units Glucarpidase or 20 units/kg in pts weighing > 100 kg is injected 24 hours after start of the HD-MTX administration. MTX and MTX metabolites are closely monitored in acidified plasma samples using combined high performance liquid chromatography and mass spectrometry (LC-MS). Results: Currently, 4 pts have been enrolled and treated at the MTX dose level of 3.0 g/m2. Of these, 2 pts completed 6 HD-MTX courses and 2 pts have completed so far 2 and 4 courses, respectively. Glucarpidase administration resulted in a rapid and pronounced reduction of MTX blood levels (> 97%) within 15 minutes and in all 12 treatment cycles. Treatment intervals ranged from 12 to 32 days, including 2 intervals longer than 28 days due to infectious complications (respiratory syncytial virus pneumonia, N=1; urinary tract infection, N=1). Noteworthy, no deterioration of kidney function was observed. Hypersensitivity reactions occurred in 3 of 4 pts in treatment cycles 3 or 4 onwards, requiring therapeutic intervention and subsequent prophylaxis. The 2 pts, who completed 6 HD-MTX courses, experienced a complete remission of their lymphoma. Summary/Conclusion: These first data demonstrate that treatment with HD-MTX and Glucarpidase is feasible in pts with CNSL and impaired renal function. However, the available data are currently limited and the first HD-MTX escalation step has not yet been reached. The observed hypersensitivity reactions are possibly due to antibody formation, which will be further investigated and prophylactic measures at least beyond the first treatment cycle will be considered.